tbuckley/cabot-search huggingface dataset:
Spatiotemporal spread of tick-borne encephalitis in the EU/EEA, 2012 to 2020
Authors: Jasper Van Heuverswyn, Luisa K. Hallmaier-Wacker, Julien Beauté, Joana Gomes Dias, Joana M Haussig, Kristina Busch, Jana Kerlik, Mateusz Markowicz, Henna Mäkelä, Teresa Marie Nygren, Hana Orlíková, Maja Socan, Jakub Zbrzeźniak, Milda Žygutiene, Céline M Gossner
Journal: Eurosurveillance (2023)

BackgroundTick-borne encephalitis (TBE) is a vaccine-preventable disease involving the central nervous system. TBE became a notifiable disease on the EU/EEA level in 2012.AimWe aimed to provide an updated epidemiological assessment of TBE in the EU/EEA, focusing on spatiotemporal changes.MethodsWe performed a descriptive analysis of case characteristics, time and location using data of human TBE cases reported by EU/EEA countries to the European Centre for Disease Prevention and Control with disease onset in 2012-2020. We analysed data at EU/EEA, national, and subnational levels and calculated notification rates using Eurostat population data. Regression models were used for temporal analysis.ResultsFrom 2012 to 2020, 19 countries reported 29,974 TBE cases, of which 24,629 (98.6%) were autochthonous. Czechia, Germany and Lithuania reported 52.9% of all cases. The highest notification rates were recorded in Lithuania, Latvia, and Estonia (16.2, 9.5 and 7.5 cases/100,000 population, respectively). Fifty regions from 10 countries, had a notification rate ≥ 5/100,000. There was an increasing trend in number of cases during the study period with an estimated 0.053 additional TBE cases every week. In 2020, 11.5% more TBE cases were reported than predicted based on data from 2016 to 2019. A geographical spread of cases was observed, particularly in regions situated north-west of known endemic regions.ConclusionA close monitoring of ongoing changes to the TBE epidemiological situation in Europe can support the timely adaption of vaccination recommendations. Further analyses to identify populations and geographical areas where vaccination programmes can be of benefit are needed.
Error in Byline and Author Affiliations
Journal: JAMA Network Open (2023)

Samilia Obeng-Gyasi, MD, MPH; Yaming Li, MD, MS; William E. Carson, MD; Sarah Reisinger, PhD; Carolyn J. Presley, MD; Peter G. Shields, MD; David P. Carbone, MD; DuyKhanh P. Ceppa, MD; Ruth C. Carlos, MD, MS; Barbara L. Andersen, PhD
CRP, C-Peptide, and Risk of First-Time Cardiovascular Events and Mortality in Early Type 2 Diabetes: A Danish Cohort Study
Authors: Anne Gedebjerg, Mette Bjerre, Alisa Devedzic Kjaergaard, Jens Steen Nielsen, Jørgen Rungby, Ivan Brandslund, Michael Maeng, Henning Beck-Nielsen, Allan Vaag, Henrik Toft Sørensen, Troels Krarup Hansen, Reimar Wernich Thomsen
Journal: Diabetes Care (2023)

OBJECTIVE We investigated the relationship between hs-CRP, a marker of low-grade inflammation, alone or in combination with C-peptide, a marker of hyperinsulinemia/insulin resistance, and risk for cardiovascular events (CVEs) and mortality in patients recently diagnosed with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS In patients with recent-onset T2D, we measured serum hs-CRP (n = 7,301) and C-peptide (n = 5,765) in the prospective Danish Centre for Strategic Research in Type 2 Diabetes cohort study. Patients with no prior CVE (n = 6,407) were followed until first myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and all patients (n = 7,301) were followed for all-cause mortality. We computed adjusted hazard ratios (aHRs) by Cox regression and tested for the interaction between hs-CRP and C-peptide. RESULTS During follow-up (median 4.8 years), high (&amp;gt;3 mg/L) versus low (&amp;lt;1 mg/L) hs-CRP was associated with increased CVE risk (aHR 1.45 [95% CI 1.07–1.96]) and with even greater risk of all-cause mortality (2.47 [1.88–3.25]). Compared with patients with low hs-CRP (≤3 mg/L) and low C-peptide (&amp;lt;1,470 pmol/L), those with high levels of both biomarkers had the highest CVE (1.61 [1.10–2.34]) and all-cause mortality risk (2.36 [1.73–3.21]). Among patients with high C-peptide, risk of CVEs did not differ by low or high hs-CRP, whereas risk of all-cause mortality did. CONCLUSIONS The finding of high hs-CRP as a stronger prognostic biomarker of all-cause mortality than of CVEs may facilitate improved early detection and prevention of deadly diseases besides CVEs. Conversely, elevated C-peptide as a strong CVE biomarker supports the need to target hyperinsulinemia/insulin resistance in T2D CVE prevention.
Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy
Authors: Monica Xiong, Chao Wang, Maud Gratuze, Fareeha Saadi, Xin Bao, Megan E. Bosch, Choonghee Lee, Hong Jiang, Javier Remolina Serrano, Ernesto R. Gonzales, Michal Kipnis, David M. Holtzman
Journal: Molecular Neurodegeneration (2023)

Abstract Background Alzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) are both characterized by amyloid-β (Aβ) accumulation in the brain, although Aβ deposits mostly in the brain parenchyma in AD and in the cerebrovasculature in CAA. The presence of CAA can exacerbate clinical outcomes of AD patients by promoting spontaneous intracerebral hemorrhage and ischemia leading to CAA-associated cognitive decline. Genetically, AD and CAA share the ε4 allele of the apolipoprotein E ( APOE ) gene as the strongest genetic risk factor. Although tremendous efforts have focused on uncovering the role of APOE4 on parenchymal plaque pathogenesis in AD, mechanistic studies investigating the role of APOE4 on CAA are still lacking. Here, we addressed whether abolishing APOE4 generated by astrocytes, the major producers of APOE, is sufficient to ameliorate CAA and CAA-associated vessel damage. Methods We generated transgenic mice that deposited both CAA and plaques in which APOE4 expression can be selectively suppressed in astrocytes. At 2-months-of-age, a timepoint preceding CAA and plaque formation, APOE4 was removed from astrocytes of 5XFAD APOE4 knock-in mice. Mice were assessed at 10-months-of-age for Aβ plaque and CAA pathology, gliosis, and vascular integrity. Results Reducing the levels of APOE4 in astrocytes shifted the deposition of fibrillar Aβ from the brain parenchyma to the cerebrovasculature. However, despite increased CAA, astrocytic APOE4 removal reduced overall Aβ-mediated gliosis and also led to increased cerebrovascular integrity and function in vessels containing CAA. Conclusion In a mouse model of CAA, the reduction of APOE4 derived specifically from astrocytes, despite increased fibrillar Aβ deposition in the vasculature, is sufficient to reduce Aβ-mediated gliosis and cerebrovascular dysfunction.
Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia
Authors: Karol Nowicki-Osuch, Lizhe Zhuang, Tik Shing Cheung, Emily L. Black, Neus Masqué-Soler, Ginny Devonshire, Aisling M. Redmond, Adam Freeman, Massimilliano di Pietro, Nastazja Pilonis, Wladyslaw Januszewicz, Maria O'Donovan, Simon Tavaré, Jacqueline D. Shields, Rebecca C. Fitzgerald
Journal: Cancer Discovery (2023)

Intestinal metaplasia in the esophagus (Barrett's esophagus IM, or BE-IM) and stomach (GIM) are considered precursors for esophageal and gastric adenocarcinoma, respectively. We hypothesize that BE-IM and GIM follow parallel developmental trajectories in response to differing inflammatory insults. Here, we construct a single-cell RNA-sequencing atlas, supported by protein expression studies, of the entire gastrointestinal tract spanning physiologically normal and pathologic states including gastric metaplasia in the esophagus (E-GM), BE-IM, atrophic gastritis, and GIM. We demonstrate that BE-IM and GIM share molecular features, and individual cells simultaneously possess transcriptional properties of gastric and intestinal epithelia, suggesting phenotypic mosaicism. Transcriptionally E-GM resembles atrophic gastritis; genetically, it is clonal and has a lower mutational burden than BE-IM. Finally, we show that GIM and BE-IM acquire a protumorigenic, activated fibroblast microenvironment. These findings suggest that BE-IM and GIM can be considered molecularly similar entities in adjacent organs, opening the path for shared detection and treatment strategies. Our data capture the gradual molecular and phenotypic transition from a gastric to intestinal phenotype (IM) in the esophagus and stomach. Because BE-IM and GIM can predispose to cancer, this new understanding of a common developmental trajectory could pave the way for a more unified approach to detection and treatment. See related commentary by Stachler, p. 1291. This article is highlighted in the In This Issue feature, p. 1275.
Enhanced Ca <sup>2+</sup> -Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation
Authors: Jordi Heijman, Xiaobo Zhou, Stefano Morotti, Cristina E. Molina, Issam H. Abu-Taha, Marcel Tekook, Thomas Jespersen, Yiqiao Zhang, Shokoufeh Dobrev, Hendrik Milting, Jan Gummert, Matthias Karck, Markus Kamler, Ali El-Armouche, Arnela Saljic, Eleonora Grandi, Stanley Nattel, Dobromir Dobrev
Journal: Circulation Research (2023)

Small-conductance Ca2+-activated K+ (SK)-channel inhibitors have antiarrhythmic effects in animal models of atrial fibrillation (AF), presenting a potential novel antiarrhythmic option. However, the regulation of SK-channels in human atrial cardiomyocytes and its modification in patients with AF are poorly understood and were the object of this study. Apamin-sensitive SK-channel current (ISK) and action potentials were recorded in human right-atrial cardiomyocytes from sinus rhythm control (Ctl) patients or patients with (long-standing persistent) chronic AF (cAF). ISK was significantly higher, and apamin caused larger action potential prolongation in cAF- versus Ctl-cardiomyocytes. Sensitivity analyses in an in silico human atrial cardiomyocyte model identified IK1 and ISK as major regulators of repolarization. Increased ISK in cAF was not associated with increases in mRNA/protein levels of SK-channel subunits in either right- or left-atrial tissue homogenates or right-atrial cardiomyocytes, but the abundance of SK2 at the sarcolemma was larger in cAF versus Ctl in both tissue-slices and cardiomyocytes. Latrunculin-A and primaquine (anterograde and retrograde protein-trafficking inhibitors) eliminated the differences in SK2 membrane levels and ISK between Ctl- and cAF-cardiomyocytes. In addition, the phosphatase-inhibitor okadaic acid reduced ISK amplitude and abolished the difference between Ctl- and cAF-cardiomyocytes, indicating that reduced calmodulin-Thr80 phosphorylation due to increased protein phosphatase-2A levels in the SK-channel complex likely contribute to the greater ISK in cAF-cardiomyocytes. Finally, rapid electrical activation (5 Hz, 10 minutes) of Ctl-cardiomyocytes promoted SK2 membrane-localization, increased ISK and reduced action potential duration, effects greatly attenuated by apamin. Latrunculin-A or primaquine prevented the 5-Hz-induced ISK-upregulation. ISK is upregulated in patients with cAF due to enhanced channel function, mediated by phosphatase-2A-dependent calmodulin-Thr80 dephosphorylation and tachycardia-dependent enhanced trafficking and targeting of SK-channel subunits to the sarcolemma. The observed AF-associated increases in ISK, which promote reentry-stabilizing action potential duration shortening, suggest an important role for SK-channels in AF auto-promotion and provide a rationale for pursuing the antiarrhythmic effects of SK-channel inhibition in humans.
Light‐Triggered Nitric Oxide Nanogenerator with High<scp>l</scp>‐Arginine Loading for Synergistic Photodynamic/Gas/Photothermal Therapy
Authors: Hui Shi, Cheng‐Feng Xiong, Lin‐Jun Zhang, Hu‐Chen Cao, Ru Wang, Pei Pan, Hai‐Yan Guo, Tao Liu
Journal: Advanced Healthcare Materials (2023)

The development of nanomedicines that combine photothermal therapy (PTT) with photodynamic therapy (PDT) is considered promising for cancer treatment, but still faces the challenge of enhancing tumoricidal efficiency. Fortunately, apart from the well-acknowledged effect on direct tumor cell-killing, nitric oxide (NO) is also considered to be effective for the enhancement of both PTT and PDT. However, both the low loading efficiency of NO precursor and the short half-life time and diffusion distance of NO hamper the synergistic therapeutic efficacy of NO. Taking the aforementioned factors into account, a mitochondria-targeted nitric oxide nanogenerator, EArgFe@Ce6, is constructed to achieve high loading of the NO donor l-Arginine (l-Arg) for synergistic photodynamic/gas/photothermal therapy upon single 660 nm light irradiation. The coordination of epigallocatechin gallate (EGCG) and ferric ions (Fe3+ ) provides EArgFe@Ce6 supreme photothermal capability to perform low-temperature PTT (mPTT). EGCG endows EArgFe@Ce6 with mitochondria-targeting capability and meanwhile favors hypoxia alleviation for enhanced PDT. The PDT-produced massive reactive oxygen species (ROS) further catalyzes l-Arg to generate a considerable amount of NO to perform gas therapy and sensitize both mPTT and PDT. In vitro and in vivo studies demonstrate that the synergistic photodynamic/gas/photothermal therapy triggered by single 660 nm light irradiation is highly effective for tumor treatments.
Development of a Framework for Addressing Skin Biopsy Tray Waste in Dermatology Clinics
Authors: Paige W. Wolstencroft, Natasha C. Zacher, Katie Scotellaro, Sierra Centkowski, Bernice Y. Kwong
Journal: JAMA Dermatology (2023)

The US health care system generates substantial global waste. Skin biopsies are frequently performed by dermatologists and represent a practical and scalable opportunity for waste reduction interventions in dermatology clinics.
The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment
Authors: Paola Facheris, Jane Jeffery, Ester Del Duca, Emma Guttman-Yassky
Journal: Cellular and Molecular Immunology (2023)

Atopic dermatitis (AD) is the most common inflammatory skin disease, and it is considered a complex and heterogeneous condition. Different phenotypes of AD, defined according to the patient age at onset, race, and ethnic background; disease duration; and other disease characteristics, have been recently described, underlying the need for a personalized treatment approach. Recent advancements in understanding AD pathogenesis resulted in a real translational revolution and led to the exponential expansion of the therapeutic pipeline. The study of biomarkers in clinical studies of emerging treatments is helping clarify the role of each cytokine and immune pathway in AD and will allow addressing the unique immune fingerprints of each AD subset. Personalized medicine will be the ultimate goal of this targeted translational research. In this review, we discuss the changes in the concepts of both the pathogenesis of and treatment approach to AD, highlight the scientific rationale behind each targeted treatment and report the most recent clinical efficacy data.
What's Next for Sotorasib in NSCLC?
Journal: Cancer Discovery (2023)

The CodeBreaK 200 trial showed that sotorasib led to a 34% decrease in relative risk of disease progression or death compared with docetaxel but yielded no improvement in overall survival. Despite the KRAS inhibitor's high cost, less toxicity likely tips the balance in its favor. Subgroup analyses and combination trials are underway to optimize treatment with sotorasib and other KRAS inhibitors.
Role of Tumor Necrosis Factor–α Inhibitors in the Treatment and Occurrence of Acne
Authors: Aaron Gabriel W. Sandoval, Lauren T. Vaughn, Jennifer T. Huang, John S. Barbieri
Journal: JAMA Dermatology (2023)

Tumor necrosis factor-α inhibitors (TNFis) approved to treat several inflammatory diseases are sometimes used off label to treat severe forms of acne that are refractory to conventional therapies. However, use of TNFis can also be followed by acne occurrence, suggesting an association between TNFis and acne. Most of the literature on the topic comprises case reports and series that have not been reviewed in a systematic manner.
Thiazides Attenuate Insulin Secretion Through Inhibition of Mitochondrial Carbonic Anhydrase 5b in β-Islet Cells in Mice
Authors: Patrycja Kucharczyk, Giuseppe Albano, Christine Deisl, Tin Manh Ho, Matteo Bargagli, Manuel Anderegg, Stephan Wueest, Daniel Konrad, Daniel G. Fuster
Journal: Journal of the American Society of Nephrology (2023)

Thiazide diuretics (thiazides) are among the most widely prescribed drugs worldwide, but their use is associated with glucose intolerance and new-onset diabetes mellitus. The molecular mechanisms remain elusive. Our study reveals that thiazides attenuate insulin secretion through inhibition of the mitochondrial carbonic anhydrase isoform 5b (CA5b) in pancreatic β cells. We furthermore discovered that pancreatic β cells express only one functional carbonic anhydrase isoform, CA5b, which is critical in replenishing oxaloacetate in the mitochondrial tricarboxylic acid (TCA) cycle (anaplerosis). These findings explain the mechanism for thiazide-induced glucose intolerance and reveal a fundamental role of CA5b in TCA cycle anaplerosis and insulin secretion in β cells.
Impact of U2AF1 mutations on circular RNA expression in myelodysplastic neoplasms
Authors: Eileen Wedge, Ulvi Ahmadov, Thomas B. Hansen, Zongliang Gao, Morten Tulstrup, Christophe Côme, Sridhar Nonavinkere Srivatsan, Tanzir Ahmed, Jakob S. Jespersen, Balthasar C. Schlotmann, Claudia Schöllkopf, Klas Raaschou-Jensen, Niels Ødum, Jørgen Kjems, Rasmus O. Bak, Matthew J. Walter, Kirsten Grønbæk, Lasse S. Kristensen
Journal: Leukemia (2023)
Using an influenza surveillance system to estimate the number of SARS-CoV-2 infections in Beijing, China, weeks 2 to 6 2023
Authors: Li Zhang, Yi Zhang, Wei Duan, Shuangsheng Wu, Ying Sun, Chunna Ma, Quanyi Wang, Daitao Zhang, Peng Yang
Journal: Eurosurveillance (2023)

With COVID-19 public health control measures downgraded in China in January 2023, reported COVID-19 case numbers may underestimate the true numbers after the SARS-CoV-2 Omicron wave. Using a multiplier model based on our influenza surveillance system, we estimated that the overall incidence of SARS-CoV-2 infections was 392/100,000 population in Beijing during the 5 weeks following policy adjustment. No notable change occurred after the Spring Festival in early February. The multiplier model provides an opportunity for assessing the actual COVID-19 situation.
Letter to the Editor: Hepatic steatosis and glycemic burden in chronic hepatitis B
Authors: Shang-Chin Huang, Jia-Horng Kao
Journal: Hepatology (2023)

To the editor, We read with great interest the study by Mak et al.1 The authors prospectively enrolled 671 chronic hepatitis B (CHB) patients with type 2 diabetes mellitus and found a positive association between high glycemic burden and HCC development as well as fibrosis progression. Notably, a nonlinear effect of glycemic burden was disclosed in the restricted cubic spline analyses. It would be interesting and important to explore whether the paradoxically lower risk of HCC in the outliers with higher glycemic burden was confounded by concomitant hepatic steatosis. In the authors' previous study using the same CHB cohort,2 more severe hepatic steatosis defined by high controlled attenuation parameter (CAP) was significantly associated with a lower risk of HCC, implying fatty liver may be a protective factor in CHB. In the current study, patients with type 2 diabetes mellitus had a higher CAP, which was a neutral factor (HR=0.997) for HCC in the univariable analysis. Since type 2 diabetes mellitus was a risk factor for HCC, it is plausible that the protective effect of high CAP was offset by the accompanying glycemic burden. Taken together, the readers may have an interest in learning whether the paradoxically lower risk in the outliers with the higher glycemic burden (who tended to have a high CAP) would remain after adjustment for steatosis and whether a high CAP was a protective factor in the multivariable analysis, as was observed in their earlier study.2 In summary, Mak and colleagues are congratulated for the excellent research highlighting the key role of glycemic control in preventing adverse liver outcomes. Investigating the interaction and the exact impacts of modifiable metabolic factors and hepatic steatosis on CHB may provide crucial insights into the optimal management strategy in our daily clinical practice.
Engineered Macrophages‐Based uPA‐Scavenger Load Gemcitabine to Prompt Robust Treating Cancer Metastasis
Authors: Zhiping Rao, Chuanchuan Lu, Hongyu Fan, Fuyu Du, Yutong Zhu, Yuqiong Xia, Zhiming Wang, Pengbo Ning
Journal: Advanced Healthcare Materials (2023)

The majority of cancer patients die of metastasis rather than primary tumors, and most patients may have already completed the cryptic metastatic process at the time of diagnosis, making them intractable for therapeutic intervention. The urokinase-type plasminogen activator (uPA) system is proved to drive cancer metastasis. However, current blocking agents such as uPA inhibitors or antibodies are far from satisfactory due to poor pharmacokinetics and especially have to face multiplex mechanisms of metastasis. Herein, an effective strategy is proposed to develop a uPA-scavenger macrophage (uPAR-MΦ), followed by loading chemotherapeutics with nanoparticles (GEM@PLGA) to confront cancer metastasis. Interestingly, significant elimination of uPA by uPAR-MΦ is demonstrated by transwell analysis on tumor cells in vitro and enzyme-linked immunosorbent assay detection in peripheral blood of mice with metastatic tumors, contributing to significant inhibition of migration of tumor cells and occurrence of metastatic tumor lesions in mice. Moreover, uPAR-MΦ loaded with GEM@PLGA shows a robust antimetastasis effect and significantly prolonged survival in 4T1-tumor-bearing mice models. This work provides a novel living drug platform for realizing a potent treatment strategy to patients suffering from cancer metastasis, which can be further expanded to handle other tumor metastasis markers mediating cancer metastasis.
The era of cryptic exons: implications for ALS-FTD
Authors: Puja R. Mehta, Anna-Leigh Brown, Michael E. Ward, Pietro Fratta
Journal: Molecular Neurodegeneration (2023)

Abstract TDP-43 is an RNA-binding protein with a crucial nuclear role in splicing, and mislocalises from the nucleus to the cytoplasm in a range of neurodegenerative disorders. TDP-43 proteinopathy spans a spectrum of incurable, heterogeneous, and increasingly prevalent neurodegenerative diseases, including the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum and a significant fraction of Alzheimer’s disease. There are currently no directed disease-modifying therapies for TDP-43 proteinopathies, and no way to distinguish who is affected before death. It is now clear that TDP-43 proteinopathy leads to a number of molecular changes, including the de-repression and inclusion of cryptic exons. Importantly, some of these cryptic exons lead to the loss of crucial neuronal proteins and have been shown to be key pathogenic players in disease pathogenesis (e.g. , STMN2 ), as well as being able to modify disease progression (e.g. , UNC13A ). Thus, these aberrant splicing events make promising novel therapeutic targets to restore functional gene expression. Moreover, presence of these cryptic exons is highly specific to patients and areas of the brain affected by TDP-43 proteinopathy, offering the potential to develop biomarkers for early detection and stratification of patients. In summary, the discovery of cryptic exons gives hope for novel diagnostics and therapeutics on the horizon for TDP-43 proteinopathies.